Call it “The Case of the Dueling Genes.” A woman at high risk for early-onset Alzheimer’s disease because of an inherited genetic mutation unexpectedly stayed dementia-free for decades, and investigators believe a different genetic mutation may have protected her—providing potential clues for an Alzheimer’s treatment.
The woman’s family carries a genetic mutation known to cause early-onset Alzheimer’s. However, she did not develop signs of the disease until her 70s, nearly 30 years after the expected onset. Researchers suspect she may have been protected because she also had two copies of the APOE3 Christchurch (APOE3ch) gene variant. Findings of a case study published in Nature Medicine suggest that two copies of the APOE3ch variant may protect against Alzheimer’s.
Early-onset Alzheimer’s is rare, representing less than 10% of all people who have the disease. Risk for both early- and late-onset Alzheimer’s disease is affected by genetic factors.
For the study, investigators at Massachusetts General Hospital, in collaboration with other researchers from Colombia, Boston, and Phoenix, looked at genetic data from a Colombian family with more than 6,000 living members. Family members who carry a rare gene mutation called Presenilin 1 (PSEN1) E280A have a 99.9% risk of developing early-onset Alzheimer’s disease.
This woman carried the PSEN1 E280A mutation. However, she also had two copies of the APOE3ch gene variant, unlike any other affected relative. Imaging tests showed that she had large amounts of amyloid protein deposits, a hallmark of Alzheimer’s disease, in her brain. But the amount of tau tangles, another hallmark of the disease—and the one more correlated with how thinking and memory are affected—was relatively low.
Experiments as part of the study showed that the APOE3ch variant may reduce the ability of APOE to bind to certain sugars called heparan sulphate proteoglycans (HSPG). APOE binding to HSPG has been implicated as one mechanism that may contribute to the amyloid and tau protein deposits that destroy the brain. The research suggests that a drug or gene therapy that could reduce APOE and HSPG binding has the potential to be a new way to treat or prevent Alzheimer’s disease.
The study was funded in part by the National Institute on Aging.
Source: NIH, November 4, 2019